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Abstract Number: 1706

Prevention of SU5416-Induced Pulmonary Hypertension in a TGFβ Dependent Genetic Mouse Model of Scleroderma Using the Endothelin Receptor Antagonist Macitentan

Emma C. Derrett-Smith1, Vincent Sobanski2, Sarah Trinder3, Adrian J Gilbane3, Marc Iglarz4, David J. Abraham3, Alan M. Holmes5 and Christopher P Denton6, 1Centre for Rheumatology and Connective Tissue Diseases,, UCL Medical School Royal Free Campus, London, United Kingdom, 2UCL Medical School, London, United Kingdom, 3Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, London, United Kingdom, 4Actelion Pharmaceuticals Ltd., Allschwil, Switzerland, 5Centre for Rheumatology and Connective Tissue Diseases, UCL, London, United Kingdom, 6Centre for Rheumatology and Connective Tissue Disease, UCL Medical School Royal Free Campus, London, United Kingdom

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Animal models, growth factors, Pulmonary complications and scleroderma

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Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Pulmonary arterial hypertension (PAH) is an important complication of systemic sclerosis (SSc) that occurs in around 10% of cases.  We have previously shown that a TGFbeta dependent transgenic mouse strain (TβRIIΔk-fib) is susceptible to organ based pathology relevant to SSc and that pulmonary endothelial injury is associated with development of PH with perturbed VEGF, BMP and endothelin signalling. In this study, we have prevented the development of PH in this mouse strain using macitentan, a potent endothelin receptor antagonist recently licensed to treat PAH in connective tissue disease based upon a significant effect on morbidity and mortality in PAH.

Methods: SU5416, a VEGF receptor inhibitor, was administered to all TβRIIΔk-fib transgenic (TG) mice and littermate wildtype (WT) animals to induce endothelial injury with subsequent endoluminal proliferation and PH in transgenic mice only. Mice were treated with either 50mg/kg macitentan daily by oral gavage or vehicle alone (n=8 each group). The development of PH in each group was assessed by histology and immunohistochemistry of vessel architecture, in vivo haemodynamic studies and RV mass index measurements.

Results: Compared with WT littermates, after SU5416, all TG mice developed a prominent perivascular chronic inflammatory infiltrate and smooth muscle layer hypertrophy, as previously described. RV mass index was elevated in TG animals receiving vehicle compared to other groups (TG vehicle 0.29±0.007, TG macitentan 0.24±0.007, p<0.05). The increase in RV systolic pressure in TG animals treated with SU5416 was also abrogated by macitentan (figure 1) without any significant change in systemic arterial blood pressure in any group. Explanted TG lung fibroblasts showed an increase in proliferation and migration with upregulation of VEGF and TGFbeta signalling and downregulation of endothelin receptor A compared with WT littermates. There was obliterative pulmonary arteriolar occlusion in 21% of vessels in TG mice treated with vehicle. In contrast, no vessels in WT mice or TG mice treated with macitentan developed this histological change.

Conclusion: Macitentan prevents the development of histological and haemodynamic PH in this mouse model of SSc.  These findings support a pivotal role for perturbed endothelin activity in a model that is induced by altered TGFbeta signalling and triggered by experimental VEGF inhibition. It underpins the value of this model as a platform for experimental therapeutic studies as well as providing insight into pathogenic mechanisms of disease.

 


Disclosure:

E. C. Derrett-Smith,
None;

V. Sobanski,
None;

S. Trinder,
None;

A. J. Gilbane,
None;

M. Iglarz,

Actelion Pharmaceuticals Ltd,

3;

D. J. Abraham,
None;

A. M. Holmes,
None;

C. P. Denton,

Actelion Pharmaceuticals Ltd,

2,

Actelion Pharmaceuticals Ltd,

5.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/prevention-of-su5416-induced-pulmonary-hypertension-in-a-tgf%ce%b2-dependent-genetic-mouse-model-of-scleroderma-using-the-endothelin-receptor-antagonist-macitentan/

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